Synthesis with cysteine

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

Sanchez-Cano et al. have proposed paired synthesis for obtaining L-cysteic acid and L-cysteine from L-cystine which greatly improves the economical parameters [57], The global process-flow for the paired synthesis, with L-cystine and water as starting materials is shown in Fig. 3. Table 2 compares the results for the paired (B) and the individual syntheses (A, C). 

Cysteine contributes sulphur atoms to chelators, and therefore the synthesis of cysteine is a further important control point. Cysteine synthase (CSase) is the final enzyme in the biosynthetic pathway. Kawashima and colleagues (2004 and references therein) have produced tobacco plants with altered levels of this protein in the cytosol and/or chloroplasts. All transformants showed enhanced tolerance to Cd, Se and Ni, but not to Pb or Cu. In particular, the plants expressing CSase both in the cytosol and the chloroplasts had an even higher Cd tolerance, and possessed enhanced levels of Cys and GSH. The same plants also accumulated more Cd. 

As discussed above, proteases are peptide bond hydrolases and act as catalysts in this reaction. Consequently, as catalysts they also have the potential to catalyze the reverse reaction, the formation of a peptide bond. Peptide synthesis with proteases can occur via one of two routes either in an equilibrium controlled or a kinetically controlled manner 60). In the kinetically controlled process, the enzyme acts as a transferase. The protease catalyzes the transfer of an acyl group to a nucleophile. This requires an activated substrate preferably in the form of an ester and a protected P carboxyl group. This process occurs through an acyl covalent intermediate. Hence, for kineticmly controlled reactions the eii me must go through an acyl intermediate in its mechanism and thus only serine and cysteine proteases are of use. In equilibrium controlled synthesis, the enzyme serves omy to expedite the rate at which the equilibrium is reached, however, the position of the equilibrium is unaffected by the protease. 

Peptide Synthesis with S-Famesylated Cysteine Derivatives and Cysteine... 

Figure 25-6 Postulated pathways for synthesis of the black pigment melanin and pigments (phaeomelanins) of reddish hair and feathers. Dopachrome reacts in two ways, with and without decarboxylation. The pathway without decarboxylation is indicated by green arrows. To the extent that this pathway is followed the green carboxylate groups will remain in the polymer. The black eumelanin is formed by reactions at the left and center while the reddish phaeomelanin is derived from polymers with cysteine incorporated by reactions at the right.

Extensive studies of enzyme-substrate complexes by resonance Raman spectroscopy (RR) have prompted the synthesis of new peptide bond modifications such as thionoesters and dithioesters (Scheme l7)t82-83l within simple model substrates. The resulting acyl-enzyme complexes are especially amenable to RR analysis with cysteine proteases such as papain due to formation of the transient dithioester intermediates. 

Pal et al. <88MI 719-02) have reported a synthesis of pyrimido[5,4-6][l, 4]thiazine nucleosides 5-bromo- or 5-iodo-deoxycytidine undergo 100% dehalogenation to 2 -deoxycytidine on heating with cysteine in 1 N aqueous potassium carbonate solution, whereas l-methyl-5-chlorocytosine undergoes very little dehalogenation forming the cyclocondensation products (270) and (271) besides uncondensed products. 

Catechol oxidation catalyzed by peroxidases can be used not only for the synthesis of sulfur-substituted catechols but also for the preparation of synthetic compounds related to pheomelanins, which contain benzothiazine units. In fact, the quinone undergoes an extremely easy nucleophilic addition by thiols. For example, treating the neurotransmitter dopamine with cysteine, in the presence of HRP/H2O2, gives rise to 2-S- and 5-5-cysteinyl-catecholamine and a smaller amount of the 2-S,5-S,-di-cysteinyl-catecholamme conjugate [48, 49] (Fig. 6.3e). 

Enzymes present in melanosomes synthesize two types of melanin, eumelanin and pheomelanin. Figure 2 illustrates the proposed biosynthetic pathways of eumelanin and pheomelanin. The synthesis of eumelanin requires tyrosinase, an enzyme located in melanosomes. Tyrosinase catalyzes the conversion of tyrosine to dopa, which is further oxidized to dopaquinone. Through a series of enzymatic and nonenzymatic reactions, dopaquinone is converted to 5,6-indole quinone and then to eumelanin, a polymer. This polymer is always found attached to proteins in mammalian tissues, although the specific linkage site between proteins and polymers is unknown. Polymers affixed to protein constitute eumelanin, but the exact molecular structure of this complex has not been elucidated. Pheomelanin is also synthesized in melanosomes. The initial steps in pheomelanin synthesis parallel eumelanin synthesis, since tyrosinase and tyrosine are required to produce dopaquinone. Dopaquinone then combines with cysteine to form cysteinyldopa, which is oxidized and polymerized to pheomelanin. The exact molecular structure of pheomelanin also has not been determined. 

Taurine is a dietary essential in the cat, which is an obligate carnivore with a limited capacity for taurine synthesis from cysteine. On a taurine-free diet, neither supplementary methionine nor cysteine will maintain normal plasma concentrations of taurine, because cats have an alternative pathway of cysteine metabolism reaction with mevalonic acid to yield felinine (3-hydroxy-1,1-dimethylpropyl-cysteine), which is excreted in the urine. The activity of cysteine sulfinic acid decarboxylase in cat liver is very low. 

A. Jacobi, D. Seebach, How to Stabilize or Break P-Peptidic Helices by Disulfide Bridges Synthesis and CD Investigation of P-Peptides with Cysteine and Homocysteine Side Chains Helv. Chim. Acta 1999, 82, 1150- 1172. 

The reaction has been widely investigated for its synthetical relevance, due to the wide range of reagents that may be employed and to the possibility of ftiriher reactions of the products so obtained, as observed, for example, in the synthesis of diazoalkanes. It is also used in biological studies with cysteine scavengers and in several different applications, which are described in the appropriate chapters. 

Peptide Synthesis with S-Protected Cysteine Derivatives... 

Reactions with aliphatic and aromatic epoxides. The metabolism of many alkenes and arenes Is known to proceed via epoxides formed by phase I reactions (166). Chemical methods for the preparation of epoxides will not be discussed here but valuable references (or references cited therein) for their synthesis are found In Table VII. The electrophilic character of the epoxides has been utilized In chemical synthesis of several PMAF metabolites. Differences In the reactlvltes of arene oxides are probably less Important In chemical synthesis of their conjugates but may Influence the ratio of positional and dlasteromers formed. The reaction of GSH with a xenobiotic epoxide gives the 1,2-dlhydro--l-hydroxy-2-glutathlonyl-xenoblotlc conjugate and with cysteine and N-acetyl-cystelne the corresponding dlhydro-hydroxy conjugates. The nucleophile (GSH, cysteine or N-acetyl-cystelne)... 

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